Developing a new therapeutic agent for retinal ciliopathies

纤毛疾病是一组重叠的临床疾病，由纤毛缺陷引起。 初生纤毛及其锚定结构，基体部。尽管个别人很少，但这群人 对人口遗传病负担有很大贡献，一些估计认为 他们的总发病率高达1：1000。重要的是，尽管一些纤毛疾病 致命的，大多数患者活到成年，在那里他们面临着深刻的临床 管理多种症状的挑战，包括视网膜变性、神经认知 缺陷、肥胖、糖尿病和精神疾病。目前，还没有治疗方法和 最少的姑息选择。这项提案旨在迈出临床开发的第一步。 渴望减缓或阻止纤毛病变退行性方面的资产。我们的工作是 基于两个关键观察结果。首先，最近的几项研究表明，睫毛病 蛋白质调节蛋白酶体介导的信号成分的选择性降解。 其次，最近在人类细胞中的全基因组抑制子筛查显示，抑制 去泛素酶USP35可改善纤毛病变所致的信号传导缺陷。正在验证 在Bardet-Biedl的三个斑马鱼模型中观察、抑制或缺失USP35 综合征(BBS)是一种典型的纤毛疾病，可使几种致病表型减弱，大多数 光感受器有明显的结构和运输缺陷，没有明显的毒副作用 效果。这些发现和模型为雷辛多的形成奠定了基础 Treateutics是一家生物技术公司，其使命是开发抑制物筛查和 衍生分子作为合理的治疗剂。在过去的一年里，雷辛多 开发了两种具有潜在临床应用价值的试剂：一种表达 针对人和小鼠USP35的shRNA及其反义寡核苷酸 目标。在这里，我们的目标是测试这些工具在人类细胞和小鼠模型中作为一种 设计临床试验的准备工作。在我们公司内部，我们将测试每种药物的疗效 一种试剂，用于减弱原代细胞中旁分泌信号的产生，这些细胞来自于 三个不同的论坛基因。同时，并与Arshavsky实验室合作 杜克，我们将测试每种试剂是否能在衰减或 消除BBS小鼠模型中光感受器的进行性丧失。成功 这些研究的完成将为未来试验的合理设计提供必要的数据 并将代表着朝着开发第一批治疗纤毛疾病的资产迈出的关键一步。

The ciliopathies are a group of >100 overlapping clinical disorders caused by defects in the primary cilium and its anchoring structure, the basal body. Although individually rare, this group contributes significantly to the population genetic disease burden, with some estimates placing their combined incidence to as much as 1:1000. Importantly, although some ciliopathies are lethal, most patients survive to adulthood, where they are faced with profound clinical challenges of managing multiple symptoms that include retinal degeneration, neurocognitive defects, obesity, diabetes and psychiatric illness. At present, there are no treatments and minimal palliative options. This proposal aims to take the first steps towards developing clinical assets that aspire to slow or arrest degenerative aspects of the ciliopathy pathology. Our work is grounded on two key observations. First, several recent studies have shown that ciliopathy proteins regulate the selective proteasome-mediated degradation of signaling components. Second, a recent genome-wide suppressor screen in human cells showed that suppression of the deubiquitinase USP35 could ameliorate ciliopathy-induced signaling defects. Validating these observations, suppression or deletion of USP35 in three zebrafish models of Bardet-Biedl syndrome (BBS), a model ciliopathy, attenuated several pathognomonic phenotypes, most prominently structural and trafficking defects in the photoreceptor with no apparent toxic side effects. These discoveries and models have been foundational to the formation of Rescindo Therapeutics, a biotech company whose mission is to develop suppressor screens and derivative molecules as rational therapeutic agents. During the past year, Rescindo has developed two reagents of potential clinical utility: an adeno-associated virus expressing shRNAs against human and mouse USP35 and antisense oligonucleotides against the same target. Here, we aim to test the utility of these tools in human cells and in mouse models as a pre-amble to designing clinical trials. Within our company, we will test the efficacy of each reagent to attenuate paracrine signaling in primary cells derived from patients with mutations in three different BBS genes. In parallel, and in collaboration with the Arshavsky laboratory at Duke, we will test whether each reagent can have a quantitative benefit in attenuating or extinguishing the progressive loss of photoreceptors in a mouse mode of BBS. Successful completion of these studies will provide the necessary data for the rational design of future trials and will represent a key step towards developing the first therapeutic assets for ciliopathies.